Supernucleophilic 4-substituted-pyridine catalysts, and processes useful for preparing same

ABSTRACT

A process of preparing 4-substituted pyridine compounds via pyridine betaine compounds.

REFERENCE TO RELATED APPLICATIONS

This is a 371 of PCT/US98/16024 filed Jul. 31, 1998, which claims thebenefit of priority to provisional application 60/054,473 filed Aug. 1,1997 and provisional application 60/055,086 filed Aug. 1, 1997. Theentire disclosure of which is hereby incorporated by reference.

BACKGROUND OF THE INVENTION

The present invention resides generally in the field of the preparationand use of 4-substituted pyridine compounds, and in particular to novelforms of supernucleophilic 4-substituted pyridine catalysts, andnucleophilic substitution processes useful for preparing such catalystsand other 4-substituted pyridines.

As further background, it is well known that many pyridines carrying anamino (desirably tertiary amino) group at the 4-position possesssupernucleophilic properties making them highly advantageous for use ascatalysts in acylation and other reactions. For example, the compound4-N,N-dimethylaminopyridine (DMAP) is used on a large scale worldwidefor acylation and other reactions in the pharmaceutical and agriculturalindustries. Historically, the preparation of 4-substituted pyridinessuch as DMAP has presented several challenges.

For example, tremendous research efforts worldwide have been made todiscover effective means for transforming one group at the 4-position ofthe pyridine ring for another. Early on, researchers were hopeful thatdirect exposure of the free pyridine base to appropriate reagents wouldresult in the effective modification of the 4-position. It has turnedout, however, that most modifications of interest at the 4-positionoccur only at the cost of extreme conditions. For instance,2-bromopyridine can be converted to 2-aminopyridine by reaction withammonium hydroxide, but only at high temperatures of 200° C. and underpressure. Den Hertog et al., Rec. Trav. Chim., 51, 381 (1932).Similarly, dimethylamine reacts with 4-chloropyridine only underpressure and at a temperature of 150° C. (L. Pentimalli, Gass. Chem.Ital., 94, 902 (1964)), a process unsuitable for commercial scale.Likewise unsuitable for commercial scale is the reaction of sodium orpotassium amide and metal methylanilides in etheral solvents or liquidammonia, as described in Hauser, J. Org. Chem., 15, 310 (1949).N-pyridyl-4-pyridinium chloride hydrochloride or 4-phenoxypyridine hasbeen reacted with nucleophiles to displace at the 4-position (D. Jerchelet al., Chem. Ber., 91, 1266 (1958)). However, these starting pyridinematerials are far removed from commerce and thus such processes would beproblematic if contemplated on a large scale.

In light of the difficulties of 4-substitution directly on the free basepyridine, a number of processes have been developed in which the4-position (or 2-position) of the pyridine ring is activated towardnucleophilic substitution by a modification of the ring nitrogen of thepyridine. Such processes are generally known asactivation-substitution-deactivation processes, and to date haveinvolved either the N-oxidation or quaternization of the pyridinesubstrate, both of which are known to activate the 2- and 4-ringpositions toward nucleophilic attack and expulsion of leaving groups atthese positions. N-oxidation as a means to activate the 2- and 4-ringpositions of pyridine has been relatively less studied thanquaternization. This may be due to the fact that the level of activationimparted by N-oxidation is lower than that of quaternization. In thelatter field, it is known that 4-substituted-pyridines such as4-cyanopyridine can be quaternized with an alkyl iodide (e.g. methyliodide) and reacted with ammonia to form a corresponding4-aminopyridine. Metzger et al., J. Org. Chem., 41 (15), 2621 (1978).The dequaternization of such alkyl quats, however, is problematic, asonly relatively exotic reagents such astriphenylphosphene/dimethylformamide (Aumann et al., J. Chem. Soc. Chem.Commun., 32, (1973)), triphenylphosphene/acetonitrile (Kutney et al.,Synth. Commun., 5 (2), 119 (1975)) anddiazabicyclononane/dimethylformamide or thiourea (Ho, Synth. Commun., 3,99 (1973)) having been reported, with each of these processes invitingsignificant difficulty on an industrial scale.

More recently, research efforts have yielded quaternary-activated4-substitution processes which can be practiced with greater advantageon a commercial scale. For example, U.S. Pat. No. 4,158,093 to Bailey etal. describes a route in which a 4-substituted pyridine base isquaternized with 2- or 4-vinylpyridine in the presence of a strong acidto yield a pyridylethyl quaternary salt. This activated quat form canthen be subjected to nucleophilic substitution at the 4-position, andsubsequently dequaternized in the presence of caustic.

U.S. Pat. Nos. 4,672,121 and 4,772,713 both to Nummy describe processesin which the 4-substituted pyridine base is reacted with acrylamide oran alkylacrylamide as the quaternizing reagent, and the resultingcarbamoyl quat or a derivative therefrom is subject to nucleophilicdisplacement at the 4-position, again followed by dequaternization. Inthese '121 and '713 patents, the quaternization is conducted in thepresence of a strong acid, and the substitution and dequaternization areconducted in the presence of a strong base such as alkali metalhydroxides or carbonates, or strong amidine bases.

The above-described research efforts have culminated in the pastdecade-and-a-half in the successful commercialization and worldwide useof the supernucleophilic catalyst, DMAP, and have opened the door toroutes to similar useful 4-substituted pyridine compounds. However,needs remain for novel and improved 4-substitution processes forpyridines, and improved product forms. Desirable processes would entailthe use of readily-available starting materials and reagents whileproviding high purity products and minimizing and/or simplifyingpurification steps. Improved processes would also minimize reagent useand the need to recycle materials or handle or dispose hazardous wastes.As well, new product forms, especially of supernucleophilic4-substituted pyridine catalysts, would avoid or reduce difficultieswhich have been encountered in the handling of crystalline or flakedcatalyst forms which have been available to date. The present inventionprovides several embodiments, each of which addresses one or more ofthese needs.

SUMMARY OF THE INVENTION

Accordingly, one feature of the present invention is the provision of asupernucleophilic 4-substituted pyridine catalyst in a unique form, anda process for making the same. The preferred process for preparing agranular supernucleophilic 4-substituted pyridine catalyst, especially amonoalkylamino- or dialkylaminopyridine catalyst, includes a step ofproviding the supernucleophilic catalyst as a molten flowable mass. Thisflowable mass is then extruded through an orifice into discrete liquidportions each corresponding to a granule to be formed. These liquidportions, in turn, are cooled to form a granular supernucleophiliccatalyst. The granular supernucleophilic catalyst, most preferably4-N,N-dimethylaminopyridine (DMAP), desirably has an average particulardiameter of about 1 to about 10 mm. Suitable melt temperatures rangefrom the melting point for the catalyst, e.g. 111-112° C. for DMAP, upto just below the decomposition temperature for the catalyst, withpreferred melt temperatures ranging from about the melting point of thecatalyst up to about 50° above that point, e.g. for DMAP about 112° C.to about 160° C., more preferably from the melting point up to about 30°C. above the melting point, and especially for DMAP about 115° C. toabout 130° C.

In still more preferred processes, the extruding step is conducted usingequipment optimally designed for forming the discreet portions. Forexample, such may involve an extrusion apparatus equipped to deliver theflowable mass through an orifice for a predetermined period of time toprovide drops of the appropriate size. This control can be achieved, forexample, by providing first and second wall members each havingorifices, wherein the wall members are movable relative to one anotherto periodically align orifices in the first member with those in thesecond member for the predetermined period of time. The flowable mass ispressurized against the first wall member such that when the orifices inthe first and second wall member are aligned, an amount of the flowablemass is extruded through the aligned orifices, for example downwardlyonto a conveyor belt. Most preferred devices for these purposes includeas the first member, a first container, e.g. a drum, filled andpressurized with the flowable mass, and as the second member a secondcontainer, e.g. a second drum, encasing the first container. Eachcontainer has orifices, and they are movable (e.g. rotatable) withrespect to one another (preferably provided by a static inner containerand a movable (rotating) outer container. Movement of the secondcontainer results in periodic alignment of the orifices for thepredetermined time, during which the drops of supernucleophilic catalystmaterial are extruded through the aligned orifices and downwardly onto apassing conveyer. Such processes provide preferred, smooth-surfacedsupernucleophilic catalyst granules of uniform size and shape, forexample generally hemispherical in shape.

Another preferred embodiment of the invention provides a catalystcomposition comprising a granulated supernucleophilic 4-(secondary ortertiary)aminopyridine catalyst, especially a dialkylaminopyridinecatalyst such as DMAP. Preferred such catalysts have an average particlediameter of about 1 mm to about 10 mm, with most preferred catalystforms having smooth granules of substantially uniform size and/or shape.

Additional preferred embodiments of the invention relate to improvedactivation-substitution-deactivation routes to 4-substituted pyridines.On such preferred embodiment involves a process for preparing a4-(secondary or tertiary)aminopyridine compound. This process includesreacting a starting 4-substituted pyridine base having a leaving groupas the 4-substituent, with an activating agent of the formula:

wherein R³ and R⁴, which may be the same as or may differ from oneanother, are each —H or a C₁-C₄ alkyl group, and Z is —OR⁷ or NR⁵R⁶,wherein R⁵ and R⁶, which may be the same as or may differ from oneanother, and may taken together form a ring, are each —H or C₁-C₈ alkyl;and R⁷ is —H or C₁-C₈ alkyl. This reacting forms an activated1,4-substituted pyridine, which is then reacted with a primary orsecondary amine in at least a 3:1 molar ratio relative to the pyridine,to form a corresponding 1-substituted,4-(secondary ortertiary)aminopyridine. The 1-substituted,4-(secondary ortertiary)aminopyridine is then treated to remove the 1-substituent andthereby form a product medium including the 4-(secondary ortertiary)aminopyridine. It has been found that by conducting thesubstitution step in the presence of a large molar excess of the amineused as the nucleophile in the substitution, the use of strong basessuch as alkali metal hydroxides in the substitution step can beminimized or eliminated, and that downstream product separations aresimplified, providing highly pure, white 4-(secondary ortertiary)aminopyridine products even absent a solvent recrystallizationstep. This process is applied with preference to a manufacture of DMAP,wherein the amine is dimethylamine. The activating agent in this processis preferably acrylic acid or acrylamide.

Another embodiment of the present invention provides anactivation-substitution-deactivation route to 4-nucleophile-substitutedpyridines, wherein the activated pyridine species is a pyridine betaine.Preferred processes include reacting a starting 4-substituted pyridinebase having a leaving group as the 4-substituent, with anα,β-unsaturated acid of the formula

wherein R³ and R⁴, which may be the same as or may differ from oneanother, are each —H or a C₁-C₄ alkyl group, so as to form acorresponding activated 1,4-substituted pyridine betaine. The betaine isreacted with a nucleophile (Nu) to displace the leaving group and form a1-substituted,4-Nu-pyridine betaine. This betaine is then treated toremove the 1-substituent from the 4-Nu-pyridine compound. Preferredprocesses of this embodiment involve activation steps conducted in theabsence of acid other than the α, β-unsaturated acid, and further thenucleophilic substitution is optionally conducted under mild basicconditions (i.e. in the absence of strong bases such as alkali metalhydroxide) in the presence of a primary or secondary amine used as thenucleophile in at least a 3:1 molar ratio relative to the pyridinebetaine. In its most desirable form to date, this process involves thereaction of 4-cyanopyridine with acrylic acid to form a correspondingbetaine. This betaine is reacted with dimethylamine to form acorresponding 4-N,N-dimethylaminopyridine betaine. This betaine is thentreated in the presence of a strong base such as sodium hydroxide toremove the 1-substituent and form DMAP.

A still further embodiment of the invention provides a novel, optionallyisolated, pyridine betaine of the formula

wherein:

G is a group selected from —CN and —NR¹R², wherein R¹ and R², which maybe the same or may differ from one another, are each —H or a hydrocarbongroup having from one to about ten carbon atoms, especially C₁-C₁₀ alkylgroups, and most preferably methyl groups; and

R³ and R⁴, which may be the same as or may differ from one another, areselected from —H and C₁-C₄ alkyl groups.

A still further preferred embodiment of the invention provides heatstable 4-(secondary or tertiary)aminopyridine catalysts which may beproduced by processes of the invention. Such heat stability can beexhibited in one or more of several ways. For example, preferredproducts, especially DMAP products, have an APHA color of less thanabout 50 and exhibit an increase in APHA color of no greater than about50 when heated in a nitrogen atmosphere at about 120° C. for about 24hours. For instance, more preferred DMAP products have an APHA color ofless than about 10, and exhibit an APHA color of no greater than about50 after heating in a nitrogen atmosphere at about 120° C. for about 24hours. In another feature demonstrating heat stability, the presentinvention provides amorphous (i.e. non-crystalline form) 4-(secondary ortertiary)aminopyridine catalysts, particularly DMAP catalysts, having anAPHA color of less than 20, more preferably less than 10.

The invention provides improved supernucleophilic catalysts and improvedsynthetic routes which can be used to prepare such catalysts and otheruseful substituted pyridines. The novel catalyst forms overcome handlingand processing difficulties previously encountered withsupernucleophilic catalysts, and preferred processes can be used toprovide high yields while employing readily available materials,minimizing the use of reagents, and/or minimizing the difficulty and/ornumber of product purification steps. Additional objects, features andadvantages of the invention will be apparent from the description thatfollows.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 is a graph of APHA color over time demonstrating heat stabilityof preferred DMAP product of the invention.

FIG. 2 is enlarged digital image of a photograph of a preferred granularDMAP catalyst product of the invention.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

For the purposes of promoting an understanding of the principles of theinvention, reference will now be made to certain preferred embodimentsthereof and specific language will be used to describe the same. It willnevertheless be understood that no limitation of the scope of theinvention is thereby intended, such alterations, further modificationsand applications of the principles of the invention as described hereinbeing contemplated as would normally occur to one skilled in the art towhich the invention relates.

As disclosed above, one preferred embodiment of the present inventionprovides novel forms of supernucleophilic catalysts. The novel forms inaccordance with the invention are granular catalysts, and are preparableby melt extrusion processes which yield discreet liquid portions whichupon solidification form smooth granules or prills.

Melt extrusion processes of the invention preferably involve theextrusion of molten 4-(secondary or tertiary)aminopyridine catalysts.Preferred catalysts for use in the invention thus include those of theformula:

wherein R¹ and R², which may be the same as or may differ from oneanother, are each —H or a hydrocarbon group having from one to about tencarbon atoms, especially —H or a C₁-C₁₀ alkyl, with the proviso that atleast one of R¹ and R² is a hydrocarbon group such as alkyl. Morepreferred catalysts occur where R¹ and R² are each alkyl, especiallylower (C₁-C₄) alkyl such as methyl. The most preferred catalyst for meltextrusion processing in accordance with the invention is DMAP (i.e., R¹and R² are both methyl).

As disclosed above, the catalyst is extruded, while molten, through anorifice in a fashion which provides granules of the desired size.Processes of the invention can, for example, be conducted in anextrusion apparatus as described in U.S. Pat. No. 4,279,579, which ishereby incorporated herein by reference in its entirety. Such anapparatus includes a first cylindrical container having a plurality oforifices and a second cylindrical container disposed within the firstcontainer and also including a plurality of orifices. Means are providedfor admitting the flowable molten mass of catalyst into the secondcontainer, and means are also provided for producing relative rotationbetween the containers to periodically align the passages of the firstcontainer with the passages of the second container, so as to depositdrops of the flowable mass through the passages downwardly onto aconveyor belt also provided in the apparatus. Such processes in whichdiscreet drops or portions are caused to solidify to form flowablegranules are generally referred to as prilling processes, and theresulting granules are referred to as prills. In the preferred process,the conveyor belt is a cooled stainless steel belt, which hastens thesolidification of the flowable mass drops as they exit the passageprovided by the aligned orifices. Suitable devices for the conduct ofsuch processes are commercially available from Sandvic Process Systems,Inc. of Totowa, N.J., U.S.A. Further information regarding such devicesis available from Sandvic's trade literature, including that entitledSandvik Rotoform® Process, Premium Pastilles at high production rates,low production costs (1993); A World of Chemical Experience in ChemicalProcessing: Sandvik Process Systems.

As indicated, the supernucleophilic catalyst is provided in a moltenstate for extrusion processing. Preferred melt processing temperatureswill range from about the melting point of the catalyst up to thedecomposition temperature of the catalyst. More preferred temperatureswill be at about the melting point up to about 50° C. above the meltingpoint of the catalyst in hand. For the most preferred catalyst, DMAP, agenerally suitable temperature range is about 112° C. to about 200° C.,and a more preferred temperature range is about 115° C. to about 130° C.In any event, the temperature utilized will be selected in light of theconditions at hand, and will be optimized to provide the desiredviscosity of the flowable catalyst mass for extrusion processing inaccordance with the invention.

Granulated catalysts in accordance with the invention will preferablyhave smooth granules with an average particle diameter of about 1 toabout 10 mm, more preferably about 1 to about 5 mm. In addition,preferred catalysts will have granules of substantially uniform shapeand size. When produced by preferred extrusion processes as describedabove, granulated catalysts of the invention will have a substantially3-dimensional shape (i.e. the deposited drops will solidify prior totheir spreading to form a substantially 2-dimensional flake), whichprovides improved flow properties for the solid catalyst in accordancewith the invention. Preferred granules so prepared will generally alsohave a relatively flat or planar surface on a first side (from contactwith the conveyor belt), and a generally arcuate surface on a secondside opposite the first side. Preferred granulated catalysts of theinvention also exhibit desirable dissolution properties in aqueousmedium, meaning that while provided in a readily handled and manipulatedgranulated form in the dry state, once placed in aqueous media, thecatalyst granules break up and dissolve into solution with relative easeand quickness, generally within about a few minutes with agitation atthe catalytic levels at which they are conventionally used (e.g. atconcentration levels less than about 10% by weight in solution). Inaddition, preferred granulated products of the invention will have a lowlevel of fines having a particle diameter of less than 600 microns, morepreferably less than 5% by weight fines, and most preferably less than3% by weight fines. Particle integrity of preferred products will alsominimize the generation of fines under conditions of abrasion andimpact. For example, preferred products will generate less than 10% byweight fines in friability testing under test methods S4-77 and/or S5-77as described further in Example 9 below, more preferably less than 5% byweight generated fines and most preferably less than 2% by weight.

The preferred granulated catalysts of the invention are free-flowing,and exhibit little to no tendency to aggregate. These catalysts thusovercome difficulties which have been encountered with prior crystallineor flaked DMAP forms, and are advantageously handled in manufacturing,storage and use operations. As illustrations, catalysts of the inventiondemonstrate advantages making them well suited for transport operationsincluding gravity flow or vacuum,(e.g. as in gravity flow addition orvacuum addition to reactors), and can optionally be packaged incontainers adapted to facilitate such operations. For instance, in thecase of gravity flow addition, granulated catalysts of the invention canbe packaged in containers that are adapted for connection to reactorports and that incorporate product release mechanisms that areactivatable upon or after such connection. Such containers may also beadapted for efficient gravity flow of the granular catalyst out of anopening of the container, and in this regard may have a shape adapted torelease all of the granular catalyst upon activation of the productrelease mechanism. To this end, the container may include one or morewall members inclined downwardly toward the opening of the containeradapted for connection to the reactor port. In this manner, safe,efficient and convenient use of granular catalysts of the invention isfacilitated.

The supernucleophilic catalyst material for use in preparingadvantageous granules of the invention may be synthesized by anysuitable route. For example, it may be prepared usingactivation-substitution-deactivation techniques described in any one ofU.S. Pat. Nos. 4,158,093, 4,672,121 or 4,772,713, each of which ishereby incorporated by reference in its entirety. The supernucleophiliccatalyst starting material may also be prepared by improved syntheticprocesses of the present invention as described below.

One preferred process of the invention involvesactivation-substitution-deactivation processes for preparing4-substituted pyridine compounds, wherein the activating agent is anacrylic derivative or analog, and wherein the substitution step isconducted in the presence of a large excess of a secondary or tertiaryamine (HNR¹R² wherein R¹ and R² are defined as above) used as thenucleophile to displace the leaving group during the substitutionreaction.

Thus, in accordance with this process of the invention, a4-L-substituted pyridine base, wherein L is a leaving group, will firstbe activated by reaction with an activating agent of the formula:

wherein R³ and R⁴, which may be the same as or may differ from oneanother, are each —H or a C₁-C₄ alkyl group, and Z is —NR⁵R⁶ or —OR⁷or,wherein R⁵ and R⁶, which may be the same as or may differ from oneanother, and may taken together form a ring, are each —H or C₁-C₈ alkyl;and R⁷ is —H or C₁-C₈ alkyl.

Advantageous activation reactions will in general employ a molar excessof the activating agent relative to the pyridine base starting materialto facilitate high levels of conversion. Accordingly, molar ratios ofactivating agent to pyridine base starting material will typically be inthe range of 1.05:1 up to about 10:1, respectively, more typically inthe range of about 1.05:1 to about 5:1. In addition, the activatingagent may contain one or more polymerization inhibitors, in order toprevent unwanted polymerization. For example, the polymerizationinhibitor may be MEAQ or a suitable thiazine compound such asphenylthiazine that is effective to prevent polymerization of theactivating agents under distillative conditions.

The activation step is preferably performed in the presence of a strongacid catalyst (pKa less than 3), for example a strong organic acid, or astrong inorganic acid such as HCl, HBr, HI, sulfuric acid or phosphoricacid. Such acids will typically be used in a molar ratio of about 1-3:1relative to the 4-L-substituted pyridine starting material, morepreferably in a slight molar excess (e.g. in a molar ratio of about1.05:1) relative to the pyridine starting material. The activationreaction is also preferably conducted under heated conditions, withtemperatures in the range of about 50° C. to about 100° being typical,more preferably in the range of about 70° C. to about 80° C. Theactivation reaction can be conducted for several hours, with about 95%+conversion being achieved in about four hours in more preferredinventive processes.

The concentration of the reaction during the activation step will varyin accordance with the particular reactants and reagents in hand, andthe optimization of this parameter will be well within the skill ofthose practiced in a relevant field. Suitable reaction concentrationswill generally provide reacted solutions containing about 10% to about60% by weight of the activated pyridine intermediate, more typically inthe range of about 30% to about 55% by weight.

Preferred products of such activation reactions will thus have theformula:

wherein:

Z, R³ and R⁴ are as defined above; and

A is an anion (provided, e.g., by the anion of the strong acidcatalyst); and

L is a leaving group such as cyano, halo (fluoro, chloro, bromo, oriodo), arylsulfonyl having from six to ten carbon atoms, optionallysubstituted with one or more alkyl groups having from one to four carbonatoms; arylsulfonyloxy having from six to ten carbon atoms;alkylsulfonyloxy having from one to eight carbon atoms; aryloxy havingfrom six to ten carbon atoms (e.g. phenoxy); arylthio having from six toten carbon atoms (e.g. phenylthio); nitro, and the like.

In accordance with the invention, the activated 1,4-L-substitutedpyridine formed in the activation step is then reacted in the presenceof a primary or secondary amine charged in at least about a 2:1 molarratio relative to the activated 1,4-substituted pyridine under mild (pHabout 8 to about 10) basic conditions at the completion of combining theactivated 1,4-substituted pyridine and the primary or secondary amine,most preferably at essentially the basic pH provided by the pyridine andprimary or secondary amine reagents, i.e. in the substantial absence ofany strong base such as sodium hydroxide in the reaction medium. Inconducting this reaction, it is generally preferred to add the activatedpyridine intermediate to an aqueous solution of the amine nucleophile,as this has been found to provide cleaner processes. Preferred aminenucleophiles for these purposes include those of the formula HNR¹R²wherein R¹ and R² are as defined above. Additional illustrative aminesinclude hydrazine, alkylene diamines of up to eight carbon atoms,dialkylenetriamines of up to sixteen carbon atoms, polyethylenimines,and the like.

In contrast to prior known processes in which sodium hydroxide orsimilar bases have been used, it has been discovered that such stronglybasic conditions can be avoided in the substitution step, and in sodoing that cleaner reacted mediums are provided downstream, which aremore readily processed to recover substantially pure 4-(secondary ortertiary)aminopyridines. More preferred substitution reactions areconducted in the presence of the primary or secondary amine in at leasta 3:1 molar ratio relative to the pyridine compound, typically in abouta 3-5:1 molar ratio. This reaction can be suitably conducted at roomtemperature (about 25° C.) or under heated conditions. For reactions atatmospheric pressure, preferred reaction temperatures will be roomtemperature up to about the boiling temperature for the lowest boilingcomponent of the reaction mixture, typically the primary or secondaryamine. For instance, in the manufacture of DMAP, the substitutionreaction is typically conducted at temperatures of to about 60-70° C.,as higher temperatures would begin to boil off the dimethylamine.

In the substitution reaction, the primary or secondary amine displacesthe leaving group “L”, losing a hydrogen atom in the process, so as toform an activated 1-substituted,4-(secondary or tertiary)aminopyridine.The extent of completion of this reaction can be monitored and theprocess taken on to the deactivation phase upon achieving sufficientconversion. In the deactivation step, the 1-substituted,4-(secondary ortertiary)aminopyridine is treated to remove the 1-substituent andthereby form a product medium including the 4-(secondary ortertiary)aminopyridine, e.g. of the formula:

wherein R¹ and R² are as defined above.

As to conditions during the deactivation step, it is preferablyconducted under basic, heated conditions. A strong base such as analkali metal hydroxide can be used to advantage in facilitating theelimination of the 1-substituent. Desirable deactivations are alsoconducted at a temperature in the range of about 80° C. to about 100°C., although higher temperatures and superatmospheric pressures may alsobe employed.

As indicated above, it has been discovered that by conducting thesubstitution step in the presence of a large molar excess of the amineused as the nucleophile, the use of strong bases such as alkali metalhydroxides in the substitution step can be minimized or eliminated, andthat downstream product separations are simplified, providing highlypure 4-(secondary or tertiary)aminopyridine products. For example, atypical reaction workup to recover the 4-(secondary ortertiary)aminopyridine product will involve an extraction of thereaction medium with a non-polar organic solvent such as toluene, todraw the 4-(secondary or tertiary)aminopyridine product into the organicsolvent layer. The organic layer is then distilled to separate thepyridine product from the organic solvent, with the solvent typicallyhaving a lower boiling point and thus being collected first overhead. Ithas been found, in accordance with the invention, that in processesconducted as described above using mild basic conditions during thesubstitution step, the distillative separation is much cleaner. Thisprovides a distinct separation of the pyridine product, which iscollected overhead immediately as a relatively pure product, as opposedto encountering a need to collect a first, more crude pyridine productfraction, followed by a relatively pure fraction. Moreover, products canbe obtained from such processes which are highly pure, as is exhibitedfor example by the recovery of white DMAP from the distillation step,even absent any subsequent solvent recrystallization. Such whiteproducts readily exhibit APHA colors of less than 50, and demonstratesuperior thermal stability as compared to DMAP products prepared byother processes, as illustrated Example 4 below and its accompanyingFIG. 1. It is thus advantageous to combine such processes withsubsequent melt-processing of the product, without the need for anyintervening crystallization. Suitable melt processing techniquesinclude, for example flaking, or extrusion granulation processes asdescribed above.

Another aspect of the present invention involves anactivation-substitution-deactivation synthetic route to 4-substitutedpyridines, in which the activated intermediate species is a pyridinebetaine. Generally speaking, these inventive processes involve anactivation step which includes reacting a starting 4-substitutedpyridine base having a leaving group as the 4-substituent, with anα,β-unsaturated acid of the formula

wherein R³ and R⁴, which may be the same as or may differ from oneanother, are each —H or a C₁-C₄ alkyl group, so as to form acorresponding activated 1,4-substituted pyridine betaine. The betaine isreacted with a nucleophilic agent (Nu-H) to displace the leaving groupand form a 1-substituted,4-Nu-pyridine betaine. This betaine is thentreated to remove the 1-substituent and form the 4-Nu-pyridine compound.

The activation steps of such processes are conducted in a mediumessentially free from acids other than the α,β-unsaturated acid, so asto enable the formation of the betaine intermediate as opposed to aquaternary salt intermediate incorporating a separate counterioncoordinated with the positively-charged pyridine ring nitrogen. Theactivation steps are desirably conducted in a molar excess of the α,β-unsaturated acid to facilitate high and more rapid conversion of thepyridine base starting material to the betaine intermediate. Suitablemolar ratios of α,β-unsaturated acid to pyridine base are about 1-5:1,respectively, with preferred ratios being about 1.1-3:1, respectively.These reactions are conducted with preference under heated conditions,for example at temperatures ranging from about 50° C. to about 100° C.,more typically from about 50° C. to about 80° C.

Reaction concentrations during the activation step will again vary inaccordance with the particular reactants and reagents in hand, and theoptimization of this parameter will be well within the purview of thoseskilled in the relevant field. Suitable reaction concentrations willgenerally provide reacted solutions containing about 10% to about 50% ofthe activated pyridine intermediate, more typically in the range ofabout 30% to about 40% by weight.

The nucleophilic substitution reaction can be conducted in conventionalfashion, e.g. in the presence of the nucleophilic reagent and addedstrong base. In so doing, it will generally be possible to use lessstrong base than in prior-known synthetic routes due to the absence ofstrong acid in the reaction medium residual from the activation step.Where the nucleophilic agent is itself basic (e.g. where it is a primaryor secondary amine), as in above-described processes, the nucleophilicsubstitution step is desirably conducted under mild basic conditions(i.e. in the absence of strong bases such as alkali metal hydroxide) inthe presence of the primary or secondary amine in at least a 2:1 molarratio relative to the pyridine betaine, more preferably at least a 3:1molar ratio, typically 3-5:1. As before, this substitution reaction canbe suitably conducted at room temperature (about 25° C.) or under heatedconditions.

The extent of completion of the substitution reaction can be monitoredand the process taken on to the deactivation step upon achievingsufficient conversion to the 1-substituted,4-Nu-pyridine intermediate.In the deactivation step, the 1-substituted,4-(secondary ortertiary)aminopyridine is treated to remove the 1-substituent andthereby form a product medium including the 4-(secondary ortertiary)aminopyridine.

The deactivation step is preferably conducted under basic, heatedconditions. As before, a strong base such as an alkali metal hydroxideand heat (e.g. about 50° C. to about 100° C.) can be used to advantagein facilitating the elimination of the 1-substituent to form the target4-Nu-pyridine compound.

Illustrative processes of this embodiment of the invention utilize4-substituted pyridine starting materials encompassed by the formula:

wherein L is a leaving group such as cyano, halo (fluoro, chloro, bromo,or iodo), arylsulfonyl having from six to ten carbon atoms, optionallysubstituted with one or more alkyl groups having from one to four carbonatoms; arylsulfonyloxy having from six to ten carbon atoms;alkylsulfonyloxy having from one to eight carbon atoms; aryloxy havingfrom six to ten carbon atoms (e.g. phenoxy); arylthio having from six toten carbon atoms (e.g. phenylthio); nitro, and the like. This startingpyridine is reacted as described above with the α,β-unsaturated acid toform a pyridine betaine intermediate of the formula:

wherein L, R³ and R⁴ are as defined above. This betaine is thensubjected to a nucleophilic substitution reaction with a nucleophilicreagent, Nu-H, of sufficient strength to displace the leaving group, L,and form a second pyridine betaine intermediate of the formula:

In turn, this intermediate is treated to remove the 1-substituent, e.g.in the presence of caustic and heat, to form a 4-substituted pyridineproduct of the formula:

More preferred processes of this embodiment of the invention areprovided where L is cyano, the nucleophile is HNR¹R² wherein R¹ and R²are as defined above, resulting in a 4-substituted pyridine product ofthe formula:

wherein R¹ and R² areas defined above. These processes provide cleandistillative separations to recover highly pure 4-substituted pyridines,which can be taken on to melt processing (e.g. flaking or melt extrusionas described above) without intervening recrystallization, to providehigh quality product forms.

In its most desirable form to date, this betaine-mediated processinvolves the reaction of 4-cyanopyridine with acrylic acid to form acorresponding pyridine betaine. This betaine is reacted withdimethylamine to form a corresponding 4-N,N-dimethylaminopyridinebetaine. This betaine is then treated in the presence of a strong basesuch as sodium hydroxide to remove the 1-substituent and form DMAP. Sucha process is illustrated in Scheme 1 below:

These processes provide substantial savings in reagents due to theabsence of strong acid in the activation step, and the consequentreduced requirements for base during the substitution and/ordequaternization steps. In addition, DMAP products produced by suchbetaine-mediated processes are highly white as recovered fromextraction/distillation steps as described above, and provideadvantageous melt-processed product forms readily having APHA colors ofless than about 50.

Activation-substitution-deactivation processes of the invention asdiscussed above can be conducted for example in batch or continuousmodes. In continuous modes, the processes may occur in continuousstirred tank reactors, tube reactors, or the like. In one preferredform, three continuous reaction zones can be established to carry outthe activation, substitution, and deactivation steps, respectively. Forexample, tube reactors may be utilized wherein the 4-L-substitutedpyridine starting material, especially 4-cyanopyridine, activatingagent, and optionally strong acid such as HCl are combined in a tubereactor and allowed to react to form the 4-L-substituted quat or betaineintermediate. In another continuous zone, e.g. in another tube reactor,the nucleophile (Nu) to substitute for the 4-L-substituent can becombined with the intermediate, and the reaction to form the4-Nu-substituted intermediate caused to proceed. In a still furtherzone, e.g. a still further tube reactor, a base (e.g. aqueous alkali oralkaline earth metal hydroxide such as NaOH) can be combined with thestream containing the 4-Nu-substituted intermediate to deactivate theintermediate and form the desired 4-Nu-substituted pyridine compound.Heat exchangers can also be used to control the heat of the reactantsin, after or between the zones. For example, heat exchangers can beincluded to add heat between the activation and substitution zonesand/or between the substitution and deactivation zones. Still further,continuous recovery operations can be performed to recover the productas it exits the continuous reaction zones. For instance, a continuousextractor can be incorporated into the continuous processing after the4-Nu-pyridine product has been formed, to extract the product from theaqueous phase present into an organic phase. In most preferredcontinuous processes, the product is DMAP, the 4-L-substituted pyridineis 4-cyanopyridine, and the nucleophile is dimethylamine.

For purposes of promoting a further understanding of the presentinvention and its advantages, the following specific Examples areprovided. It will be understood that these Examples are illustrative,and not limiting, of the present invention.

EXAMPLE 1 Production of 4-Dimethylaminopyridine Via Acrylic Acid Quat

4-Cyanopyridine (300 gm, 2.882 mole) and 32% aqueous hydrochloric acid(342.3 gm, 3.024 mole) were combined and 50% aqueous acrylic acid (415.2gm, 2.881 mole) added to the mixture with stirring. The combinedreactants were heated with stirring for four (4) hours at 70° C. Theresulting reacted mixture was then added to a 40% aqueous solution ofdimethylamine (893.6 gm, 995 ml, 7.929 mole) with continued heating andstirring for one (1) hour at 40° C. Fifty percent (50%) aqueous sodiumhydroxide (923.5 gm. 620 ml) was added to the reaction mixture withcontinued stirring and the temperature increased and maintained at 90°C. for one (1) hour. The reaction mixture was cooled to 70° C. andextracted with toluene (150 ml). After separation of layers, the aqueouslayer was extracted with a second portion of toluene (100 ml). Thetoluene layers were combined and distilled. Toluene was removed atatmospheric temperature and 4-dimethylaminopyridine distilled at reducedpressure (b.p. 190° C., 150 mmhg) to give 4-dimethylaminopyridine (299.3gm, 2.4497 mole).

EXAMPLE 2 Production of 4-Dimethylaminopyridine Via Acrylic Acid Betaine

A. Betaine Synthesis

A one liter, four neck flask was equipped with a mechanical stirrer,thermometer, and a reflux condenser. The flask was charged with4-cyanopyridine (150.0 g, 1.441 mole), water (360.0 g), and acrylic acid(166.2 g, 2.306 mole). The reaction mixture was heated to 70-75° C. andheld for 5 to 8 hours. Reaction mixtures were then allowed to cool toroom temperature and stirred overnight, or in some cases, over a weekendbefore analysis by NMR. The conversion was determined by ratioing thering protons of the betaine with those of unreacted 4-cyanopyridine, thelimiting reagent.

B. DMAP Synthesis

A two liter, four neck flask was equipped with a mechanical stirrer,reflux condenser, thermometer, and an addition funnel. The flask wascharged with 40% dimethylamine solution (488.2 g, 4.331 mole). With goodagitation, the above betaine solution (673.3 g) was added to the DMAallowing the reaction temperature to reach 45° C. max. The reactionmixture was stirred for about 15 minutes. The reaction mixture was thenheated to about 70° C. and 50% NaOH (576.8 g, 7.21 mole) was slowlyadded. As the NaOH was added, DMA was evolved from the condenser and thetemperature was held to 70-80° C. Upon completion of the NaOH addition,the reaction mixture was heated to reflux and held for one hour tospring the betaine. Alternatively, the DMAP betaine solution, at about45° C., has been placed under reduced pressure (water aspirator) and theNaOH was slowly added at the lower temperature. After the NaOH additionwas complete, the reaction mixture was heated to 70° C., while stillunder vacuum, to remove the DMA. At 70° C., the vacuum was released andthe reaction mixture heated to reflux and held for 1 to 2 hours. The hotreaction mixture, regardless of which method of DMA removal was used,was cooled to about 90° C. and extracted with toluene (2×150 ml) at70-80° C. The layers were separated and the top layers (401.4 g) werecombined for distillation. The toluene was removed by atmosphericdistillation until the pot temperature was 180° C. The pot was slowlyeased under vacuum to a pressure of about 110 mm Hg. The DMAP wasdistilled at a head temperature of about 185-190° C. until the pot wasessentially dry. The DMAP distillate (136.0 g, 1.,113 mole) representeda 77.3% yield. The distillate was crystallized from toluene as a 40 wt %solution. The crystallized product was recovered using a lab centrifugeand dried in a vacuum oven. The dried material (118.1 g, 0.967 mole)represented a 67.1% yield of crystallized material.

EXAMPLE 3 Production of 4-Dimethylaminopyridine Via Acrylamide Quat

4-Cyanopyridine (300 gm, 2.882 mole) and 32% aqueous hydrochloric acid(342.3 gm, 3.024 mole) are combined and 50% aqueous acrylamide (2.881mole) added to the mixture with stirring. The combined reactants areheated with stirring for four (4) hours at 70° C. A 40% aqueous solutionof dimethylamine (893.6 gm, 995 ml, 7.929 mole) is added to the mixturewith continued heating and stirring for one (1) hour at 40° C. Fiftypercent (50%) aqueous sodium hydroxide (923.5 gm. 620 ml) is added tothe reaction mixture with continued stirring and the temperatureincreased and maintained at 90° C. for one (1) hour. The reactionmixture is cooled to 70° C. and extracted with toluene (150 ml). Afterseparation of layers, the aqueous layer is extracted with a secondportion of toluene (100 ml). The toluene layers are combined anddistilled. Toluene is removed at atmospheric temperature and4-dimethylaminopyridine distilled at reduced pressure (b.p. 190° C., 150mmhg) to give DMAP.

EXAMPLE 4 Heat Stability Studies for DMAP

In this Example, a DMAP sample was produced essentially as described inExample 1 hereof. The sample was heated to 120-130° C., under nitrogen,and held for three days. Samples were taken on a daily basis to test forcolor degradation. The results are shown in FIG. 1. As can be seen, theproduct of Example 1 hereof had superior heat stability, having an APHAcolor of only 50 after 24 hours and of only about 150 after three daysunder these molten conditions.

Similar testing of the product of Example 3 hereof reveals that it alsopossesses superior heat stability properties.

EXAMPLE 5 Preparation of Melt-Extruded DMAP Granules

A sample of 4-dimethylaminopyridine was molten, at a temperature of115-125° C. The molten material was deposited dropwise onto a smooth,porcelain surface. The drops solidified rapidly and formed granuleswhich were generally hemispherical in shape. The granulated product wasremoved from the surface and charged to a glass container (leavingsubstantial head space) and observed for particle integrity and flowproperties. Upon agitation of the container it was found that thegranules were resistant to fracture and highly free-flowing, exhibitinglittle or no tendency to adhere to one another.

EXAMPLE 6 Automated Melt-Extrusion of DMAP Granules

4-N,N-Dimethylaminopyridine (DMAP) is produced as described inExample 1. The 4-N,N-dimethylaminopyridine distillate is maintained inthe molten state and is processed as follows (withoutrecrystallization). The molten DMAP distillate is maintained in astorage tank under a nitrogen atmosphere. The storage tank is connectedas feed to a melt extrusion apparatus, e.g., such as one available fromSandvik Process Systems, Inc., Totowa, N.J., USA, and/or described inU.S. Pat. No. 4,279,579. The apparatus includes a rotating drum withorifices through which the molten product is extruded into discreteliquid portions downwardly onto a moving, cooled stainless steelconveyor belt. The speed and direction of the belt are synchronized withthe linearized speed and direction of the orifices of the rotating drum,to provide efficient and uniform deposit of the molten material onto thebelt. The extrusion orifices are approximately 1 mm in diameter, leadingto approximately 2 to 5 mm diameter granules. The melt extrusionapparatus is operated with the DMAP at a temperature of approximately120-130° C.,and the DMAP is preferably maintained at this temperaturethrough storage and extrusion processing for no longer than about 8hours. The resulting, generally hemispherical DMAP granules have goodcolor (APHA color of about 100 or less), are hard, and have smoothsurfaces. The granules are resistant to fracture and have substantialnon-caking properties.

EXAMPLE 7 Automated Melt-Extrusion of DMAP Granules

The process of Example 6 is repeated, except that the4-dimethylaminopyridine used is prepared via the acrylamide routedescribed in Example 3. Again, the product granules have good color,integrity, and flow properties.

EXAMPLE 8 Automated Melt-Extrusion of DMAP Granules

In this example a Rotoformer available from Sandvik Process Systems,Inc., Totowa, N.J., USA, was used to prepare melt-extruded DMAP granules(prilled form). This machine generally has the features described U.S.Pat. No. 4,279,579, and is also described in Sandvik Rotoform® Process,Premium Pastilles at high production rates, low production costs (1993);A World of Chemical Experience in Chemical Processing: Sandvik ProcessSystems. The bore size on the rotating shell of the rotoformer was 1.5mil. DMAP, prepared generally as described in Example 1, was maintainedas a melt at about 120° C.-140° C. for feed to the rotoformer. Duringoperation of the machine, molten DMAP was extruded through the boresonto the cooled belt of the rotoformer, providing DMAP prills havingdiameters of about 1-4 mil. The prills were removed at the end of thebelt by a micarta laminated plastic blade, at which point the prillsexhibited a temperature of about 30° C. A digital image of a photographof representative DMAP prills is presented as FIG. 2. Upon inspection,the prills were found to be substantially uniform in shape and toexhibit excellent hardness and integrity. The prills also exhibitedlittle or no tendency to cake.

EXAMPLE 9 Friability Testing of DMAP Prills

DMAP prills prepared as in Example 8 were subjected to friabilitytesting under procedures commonly used to test sulfur and other likeparticulates. In particular, the prills were tested under the proceduresof test methods S4-77 and S5-77. These and other test methods identifiedin this Example were performed as described in Sampling and TestingSulphur Forms, published by the Sulphur Derivatives Institute of Canada,Box 9505 Bloy Valley Square 1, 830-202 Sixth Avenue, Calgary, Alberta,Canada T2P2W6. For the S4-77 method, prilled DMAP samples were ovendried at 50° C. plus or minus 5° C. to constant weight, weighed to thenearest 0.1 and air cooled. The samples were then transferred to atumbler having a diameter of 250 mm and rotated at a speed of 19 rpmplus or minus 1 rpm for a total of 450 revolutions, maintaining asubstantially uniform peripheral speed. After the prescribedrevolutions, the material was cleaned from the tumbler and its weightrecorded. The material was then subjected to dry sieve analysis todetermine particle size distribution. The results are set forth in Table1.

TABLE 1 Original Sample Tumbled Sample Sieve Size Percent RetainedPercent Retained μm Individual Cumulative Individual Cumulative 47500.00 0.00 0.00 0.00 3350 0.12 0.12 0.05 0.05 2360 14.40 14.52 8.50 8.542000 48.75 63.27 48.96 57.50 1180 26.05 89.32 29.06 86.56 600 7.64 96.9710.31 96.87 300 1.68 98.65 2.61 99.48 <300 1.35 100.00 0.52 100.00 Total100.00 462.87 100.00 449.00 Fineness FF_(o) = 4.63 FF_(t) = 4.49 Factor(FF)* Fineness Factor (FF) = Total Cumulative % retained/100 Fines(particle size < 300) Content (Original Sample) = 1.3% Fines Production= 0.03% Particle Breakdown Modulus (PBM) = (FF_(o) − FF_(t))/FF_(o) ×100 = 2.99%.

In the S5-77 test method, a cylindrical tumbler having a diameter of 711mm and length of 508 mm was used. The tumbler had a 89 mm wide shelfmounted within long the entire length of the cylinder. The tumbler wasrotated 40 times at a speed of 31 rpm plus or minus 1 rpm. The samplewas then collected and subjected to dry sieve analysis as in the S4-77method discussed above. The results are presented in Table 2.

TABLE 2 Original Sample Tumbled Sample Sieve Size Percent RetainedPercent Retained μm Individual Cumulative Individual Cumulative 47500.00 0.00 0.00 0.00 3350 0.12 0.12 0.01 0.01 2360 14.40 14.52 7.82 7.832000 48.75 63.27 48.40 56.23 1180 26.05 89.32 31.44 87.67 600 7.64 96.979.65 97.32 300 1.68 98.65 2.08 99.39 <300 1.35 462.87 0.61 100.00 Total100.00 462.87 100.00 448.44 Fineness FF_(o) = 4.63 FF_(t) = 4.48 Factor(FF)* Fineness Factor (FF) = Total Cumulative % retained/100 Fines(particle size < 300) Content, Original Sample = 1.3% Fines Production =0.6% Particle Breakdown Modulus (PBM) = (FF_(o) − FF_(t))/FF_(o) × 100 =3.12%.

The data presented in Tables 1 and 2 demonstrate that the prilled DMAPform not only has a low initial fines content but also exhibitsunexpectedly good particle integrity and resistance to fracture andfines production under conditions of abrasion and impact.

The invention has been described above in detail, with specificreference to its preferred embodiments. It will be understood, however,that a variety of modifications and additions can be made to theprocedures disclosed without departing from the spirit and scope of theinvention. Such modifications and additions are desired to be protected.In addition, all publications cited herein are indicative of the levelof skill in the relevant art, and are each hereby incorporated byreference each in their entirety as if individually incorporated byreference and fully set forth.

What is claimed is:
 1. A process for preparing a 4-substituted pyridinecompound, which comprises: first reacting a 4-substituted pyridine basehaving a leaving group as the 4-substituent, with an α-unsaturated acidof the formula

wherein R³ and R⁴, which may be the same as or may differ from oneanother, are each —H or a C₁-C₄ alkyl group; so as to form acorresponding first 1,4-substituted pyridine betaine; second reactingthe 1,4-substituted betaine with a nucleophile to displace the leavinggroup and form a second 1,4-substituted-pyridine betaine; and treatingthe second 1,4-substituted betaine to remove the 1-substituent and formthe 4-substitued pyridine compound.
 2. The process of claim 1, whereinsaid acid is acrylic or methacrylic acid.
 3. The process of claim 2,wherein said acid is acrylic acid.
 4. The process of claim 1, whereinsaid nucleophile is a primary or secondary amine which is present in atleast about a 2:1 molar ratio relative to said first 1,4-substitutedpyridine betaine.
 5. The process of claim 4, wherein the amine is adialkylamine.
 6. The process of claim 5, wherein the dialkylamine isdimethylamine.
 7. The process of claim 5, wherein said second reactingis conducted in a medium essentially free from strong base.
 8. Theprocess of claim 7, wherein said second reacting is conducted at a pHessentially as provided by the amine and the pyridine betaine.
 9. Theprocess of claim 8, wherein the amine is dimethylamine.
 10. The processof claim 1, wherein the 4-substituted pyridine base is 4-cyanopyridine.